Ocular analyte sensor

ABSTRACT

An ophthalmic lens comprising a receptor moiety can be used to determine the amount of an analyte in an ocular fluid. The receptor moiety can bind either a specific analyte or a detectably labeled competitor moiety. The amount of detectably labeled competitor moiety which is displaced from the receptor moiety by the analyte is measured and provides a means of determining analyte concentration in an ocular fluid, such as tears, aqueous humor, or interstitial fluid. The concentration of the analyte in the ocular fluid, in turn, indicates the concentration of the analyte in a fluid or tissue sample of the body, such as blood or intracellular fluid.

[0001] This application is a continuation in part of PCT applicationPCT/EP 00/0825 filed Aug. 24, 2000, now pending. An ophthalmic lenscomprising a receptor moiety can be used to determine the amount of ananalyte in an ocular fluid which is accessible to light. The receptormoiety can bind either a specific analyte or a detectably labeledcompetitor moiety. The amount of detectably labeled competitor moietywhich is displaced from the receptor moiety by the analyte is measuredand provides a means of determining analyte concentration in an ocularfluid, such as tears, aqueous humor, or interstitial fluid. Theconcentration of the analyte in the ocular fluid, in turn, indicates theconcentration of the analyte in a fluid or tissue sample of the bodythat is not as accessible, such as blood or intracellular fluid.

[0002] Various noninvasive or minimally invasive methods to measureanalytes, particularly glucose, have been described. For example, March,U.S. Pat. Nos. 3,958,560 and 4,014,321, discloses a glucose sensorwherein a patient's eye is automatically scanned using a source of lightat one side of the cornea. A sensor located at the other side of thecornea detects the light that passes through the cornea. The level ofglucose which rotates the plan of polarized light in the aqueous humorof the patient is a function of the amount of radiation detected.However, this sensor system is not necessarily specific or widelyapplicable to detection of analytes other than glucose, because it doesnot exploit the use of biological molecules which can detect glucose orother analytes in a body tissue or fluid sample. Biological molecules,as is well known, can provide very specific and sensitive detectionreagents for particular analytes.

[0003] Schultz, U.S. Pat. No. 4,344,438, discloses a system formonitoring low molecular weight compounds in blood plasma by opticalmeans, which involves a chamber which contains specific receptor sitesfor the plasma constituent to be analyzed. This system is very invasive,however, because it must be implanted within the blood stream using ahypodermic needle. The system also inherently contains the risks ofclotting around the device, obstruction, and other adverse reactions,including immune reactions, general irritation, and foreign bodyreactions.

[0004] Embodiments of the present invention overcome these disadvantagesin the prior art by employing an ophthalmic lens comprising a receptormoiety which comprises an analyte/competitor moiety binding site todetect an analyte in an ocular fluid. Concentration of a wide variety ofanalytes can be measured using an ophthalmic lens according toembodiments of the invention. Such analytes include, but are not limitedto, electrolytes and small molecules (e.g., sodium, potassium, chloride,phenylalanine, uric acid, galactose, glucose, cysteine, homocysteine,calcium, ethanol, acetylcholine and acetylcholine analogs, ornithine,blood urea nitrogen, creatinine), metallic elements (e.g., iron, copper,magnesium), polypeptide hormones (e.g., thyroid stimulating hormone,growth hormone, insulin, luteinizing hormones, chorionogonadotrophichormone), chronically administered medications (e.g., dilantin,phenobarbital, propranolol), acutely administered medications (e.g.,cocaine, heroin, ketamine), small molecule hormones (e.g., thyroidhormones, ACTH, estrogen, cortisol, estrogen, and other metabolicsteroids), markers of inflammation and/or allergy (e.g., histamine, IgE,cytokines), lipids (e.g., cholesterol), plasma proteins and enzymes(e.g., complement, coagulation factors, liver function enzymes, heartdamage enzymes, ferritin), markers of infection (e.g., virus components,immunoglobulins such as IgM, IgG, etc., proteases, protease inhibitors),and/or metabolites (e.g., lactate, ketone bodies).

[0005] Ophthalmic lenses according to embodiments of the invention canbe used to monitor the course of therapy or the level of disease inmammals, including primates and, preferably, humans. In addition,because ophthalmic lenses according to embodiments of the inventionprovide a way to detect analytes noninvasively, they provide distinctadvantages over more traditional forms of monitoring such levels.Ophthalmic lenses according to embodiments of the invention also areuseful for diagnostic purposes, for example to test for pregnancy (todetect β-HCG), to assess blood chemistry (electrolytes, Ca₂PO₄,magnesium, bilirubin, alkaline phosphatase, lactate dehydrogenase,alanine aminotransferase, etc.), and to detect infection (e.g., bydetecting components of viruses such as CMV, EBV, hepatitis, and HIV, orbacteria, such as Staphlococcus, Streptococcus, etc.). They also areuseful for monitoring blood levels of test compounds during the courseof assessing the compounds for use as potential therapeutics.

[0006] Ophthalmic lenses according to embodiments of the invention canbe worn chronically to provide repeated analyte measurements or can beworn for a single analyte measurement. Both qualitative and quantitativemeasurements can be performed.

[0007] Ophthalmic Lens

[0008] An ophthalmic lens according to embodiments of the invention canbe a removable lens, such as a contact lens, or a permanently implantedlens, such as an intraocular lens, a subconjunctival lens, or anintracorneal lens. See U.S. Ser. Nos. 60/150,792 and 60/185,980, thepatent applications the priority of which is claimed for this invention.Permanently implanted lenses are particularly well-suited for use inindividuals who have compromised ocular function (e.g., cataracts) andalso have chronic conditions which require analyte measurement, such asdiabetics.

[0009] Ophthalmic lenses can be corrective lenses or can be constructedso that they do not affect visual acuity. Contact lenses optionally cancomprise a tint and are preferably disposable, which reduces the risk ofinfection for the user. As used herein, the term “ophthalmic lens” mayalso refer to a shunt or implant that may rest in the cul de sac of theeye.

[0010] Receptor Moiety

[0011] The ophthalmic lens comprises a receptor moiety. The receptormoiety comprises a binding site for the analyte to be detected. Thebinding site also binds a moiety which competes with the analyte forbinding and is therefore referred to herein as an “analyte/competitormoiety binding site.” Binding of both the competitor moiety and theanalyte to the analyte/competitor moiety binding site is reversible. Thenature of the molecule used as the receptor moiety depends on theparticular analyte to be detected, but minimally includes that portionof the molecule which is sufficient to contain an analyte/competitormoiety binding site.

[0012] For example, if glucose is the analyte to be detected, thereceptor moiety preferably is concanavalin A (Mansouri & Schultz,Bio/Tech 2, 385, 1984), although other moieties, such as antibodies,boronic acid, a genetically engineered bacterial fluoriprotein, orglucose oxidase also can be used.

[0013] Boronic acid derivatives may also be used as competitive moietiesfor glucose, as they form covalent complexes with glucose. For example,a combination of a fluorescence moiety, such as anthracene, boronic acidand tertiary amine gives a sensor for glucose. Illustrative, but nonelimiting boronic acid compounds are listed below:

[0014] Glucose binds with the acidic boronic moiety creating afluorescent moiety.

[0015] If phenylalanine is the analyte to be detected, the receptormoiety preferably comprises the active site of phenylalaninehydroxylase. It is well within the skill of those knowledgeable in theart to determine other analyte-receptor moiety binding pairs, such asuric acid-uricase, alcohol-alcohol dehydrogenase, copper-ceruloplasmin,galactose-galactokinase, cysteine- and/or homocysteine-cystathioninesynthetase, acetylcholine-acetylcholinesterase, ornithine-diamineoxidase, and the like.

[0016] Competitor Moiety

[0017] For use in detecting an analyte, an ophthalmic lens according toembodiments of the invention preferably comprises a competitor moietyhaving a detectable label. The competitor moiety competes with theanalyte for binding to the analyte/competitor moiety binding site. Thedetectable label can intrinsically be part of the competitor moiety.Alternatively, the detectable label can be a label which is notnaturally associated with the competitor moiety but which is attached bymeans of a chemical linkage, such as a covalent bond. In preferredembodiments, the competitor moiety comprises a fluorescent label. Otherdetectable labels, such as luminescent or calorimetric labels, also canbe used.

[0018] Again, it is well within the skill of those in the art to selecta competitor moiety which will compete with an analyte for binding to aparticular analyte/competitor moiety binding site. For example,competitor moieties which can be used with the analyte-receptor moietybinding pairs disclosed above include fluorescein dextran (whichcompetes with glucose for binding to concanavalin A), fluoresceinpolyglutamylurate (which competes with uric acid for binding touricase), fluorescein nanolol (which competes with alcohol for bindingto alcohol dehydrogenase), fluorescein-glutamine phenylacetate (whichcompetes with phenylalnine for binding to phenylalanine hydroxylase),fluorescein-erythrocuprein (which competes with copper for binding toceruloplasmin), fluorescein-2,3,6-tri-O-methyl galactose (which competeswith galactose for binding to galactokinase), fluorescein-S-adenosylpolyhomocysteine (which competes with cysteine and homocysteine forbinding to cystathionine synthetase), fluoropolyglutamyl prostigmine(which competes with acetylcholine for binding to acetylcholinesterase),and fluorospermine (which competes with ornithine for binding to diamineoxidase).

[0019] Most preferably, the detectable label is more readily detectablewhen the competitor moiety is not bound to the analyte/competitor moietybinding site. Thus, fluorescent labels, such as fluorescein, indocyaninegreen, malachite green, and rhodamine, which are quenched when thecompetitor moiety is bound but are unquenched when the competitor moietyis not bound, are preferred for use in ophthalmic lenses according toembodiments of the invention.

[0020] In addition, the sensitivity of the monitor can be controlled byaltering the concentration of the detectable label. For example, thefree resonance energy transfer function, an indicator of measurementsensitivity, can be increased by increasing the concentration of thedetectable label. Thus in the case of fluorescein dextran (whichcompetes with glucose for binding to concanavalin A), increasing theconcentration of fluorescein on the competitive moiety increases therange of fluorescence intensity. Increasing the range of fluorescenceintensity increases the sensitivity of resulting measurements.

[0021] The principle is illustrated in FIG. 1. Two different fluoresceindextran compounds, each with differing fluorescein concentrations, weretested in the same glucose environments and the fluorescence intensitymeasured. Sigma FITC-Dextran has a fluorescein concentration of 2% andM.P. Fluorescein-Dextran has a fluorescein concentration of 4%. Eachsolution was measured in a fluorophotometer with variable wavelength.The first peak is characteristic of fluorescein, the second ofrhodamine. As can be seen from FIG. 1, M.P. Fluorescein-Dextran, thecompound with the higher fluorescein concentration has a greater rangeof fluorescence intensity as measured at a given wavelength than theSigma FITC-Dextran. The larger range of fluorescence gives greatersensitivity when measuring patient glucose levels.

[0022] It is important to note the purity of the competitive moiety caninfluence the activity level of the detectable label. For example, inthe case of fluorescein dextran, the relative level of monomers, dimersor tetramers can influence the sensitivity. Relatively pure levels ofdimers seem to positively influence sensitivity.

[0023] Providing Receptor and Competitor Moieties in an Ophthalmic Lens

[0024] A variety of options are available for providing the receptor andcompetitor moieties in an ophthalmic lens. Construction of various typesof ophthalmic lenses is well known in the art. Construction of contactlenses is taught, for example, in U.S. Pat. Nos. 5,965,631, 5,894,002,5,849,811, 5,807,944, 5,776,381, 5,426,158, 4,099,859, 4,229,273,4,168,112, 4,217,038, 4,409,258, 4,388,164, 4,332,922, 4,143,949,4,311,573, 4,589,964, and 3,925,178.

[0025] Construction of intraocular lens implants is taught, inter alla,in U.S. Pat. Nos. 6,051,025, 5,868,697, 5,762,836, 5,609,640, 5,071,432,5,041,133, and 5,007,928. Subconjunctival lenses are taught, forexample, in U.S. Pat. Nos. 5,476,511, 5,400,114, and 5,127,901.Intracorneal lenses are taught, inter alia, in U.S. Pat. Nos. 6,090,141,5,984,961, 5,123,921, and 4,799,931.

[0026] In one embodiment, the receptor moiety is covalently bound to theophthalmic lens material. In another embodiment, the ophthalmic lenscomprises a polymer meshwork containing pores. The pores are of a sizewhich permit the competitor moiety to bind reversibly to theanalyte/competitor moiety binding site, but which prevent the receptormoiety and the competitor moiety from diffusing out of the ophthalmiclens. Suitable polymers for this purpose are known in the art andinclude hydrogels, such as stable polymers of polyethylene glycolhydrogel (PEGH) (March et al., 2000), and modified polyvinylalcohol,such as nelfilcon A.

[0027] In another embodiment, the ophthalmic lens comprises a receptormoiety layer, a polyelectrolyte layer, and a competitor moiety layer.The polyelectrolyte layer includes one or more polyelectrolytes, whichare generally high molecular weight polymers with multiple ionic orionizable functional groups. At least one polyelectrolyte in thepolyelectrolyte layer has a charge opposite to the overall charge of thereceptor moiety and competitor moiety layers. Suitable polyelectrolytesinclude positively charged PDDA (polydiallyidimethylammonium chloride)and negatively charged PAA (polyacrylic acid). Assembly of the layers isbased upon sequential adsorption of oppositely charged polyions. Thesensor and spacing polyelectrolytes are deposited as uniform thin films(1-10 nm) in 10-15 deposition cycles onto the porous polyvinyl alcoholor hydrogen matrix, resulting in only a 100-500 nm thick coating for thesensing film, which is highly biocompatible. A typical sequence forconstruction of an ophthalmic lens suitable for glucose detectioninvolves a deposition cycle of ultrathin (1-10 nm) films of PDDA, PM,PDDA, concanavalin A, PDDA, PAA, PDDA, fluorescein dextran, PDDA, PM,PDDA, PM, concanavalin A, PAA, fluorescein dextran, PM, etc. Technologyfor constructing ophthalmic lenses comprising such layers is taught, forexample, in WO 99/35520.

[0028] An ophthalmic lens according to embodiments of the invention canbe provided in a kit, together with instructions for measuring analyteconcentration as described below. The invention provides kits which areintended for individual patient use, in which the ophthalmic lenstypically is a contact lens, as well as kits for medical practitioners,which can comprise any of the ophthalmic lenses or their equivalentsdescribed herein.

[0029] Analyte Sensor System

[0030] An ophthalmic lens according to embodiments of the invention canbe used in an analyte sensor system. The analyte sensor system comprisesan ophthalmic lens and a detector configured to detect the detectablelabel. For example, if the label is a luminescent label, the detectormay include a luminometer; if the label is a colorimetric label, thedetector may include a colorimeter; if the label is a fluorescent label,the detector may include a fluorophotometer. Construction of suchdevices is well known in the art. Light with wavelengths which willexcite the fluorescent label can be provided, for example, by a laser ora light source, such as a light-emitting diode. A fluorophotometersuitable for use with embodiments of the invention can be constructedusing a light-emitting diode from Power Technology, Inc. (Little Rock,Ark.) (see March et al., Diabetes Technol. & Ther. 2, 27-30, 2000).

[0031] The detector can be a free-standing device, a table-top device,or a hand-held device. For convenience, the detector can be aminiaturized device and may be worn or carried as a personal accessory,for example, mounted in the frame of a pair of eyeglasses, clipped to anarticle of clothing, such as a shirt or sweater, hung around the neck,worn around the wrist, or clipped to a belt or a key ring.

[0032] Using an ophthalmic lens in an analyte sensor system, asdescribed above, embodiments of the invention provides methods ofmeasuring analyte concentration in an ocular fluid. This measurementcan, in turn, be manipulated to provide a measurement of the analyte'sconcentration in a body tissue or a fluid, such as blood orintracellular fluid. The relationship between glucose concentration inthe aqueous humor and the blood, for example, is well known. SeeSüllmann, in HANDBUCH DER PHYSIOLOGISCHEN CHEMIE, Vol. II/a, p. 867 ff.,Springer, Berlin, 1956; Graymore, in THE EYE, Vol. I, p. 348, Davson,ed., Academic Press, NY, 1962; De Berardinis et al, Exp. Eye Res. 4,179, 1965; Pohjola, Acta Ophthalmologica Suppl. 88, 1966; Reim et al.,Ophthalmologica 154, 39-50, 1967; Kinsey & Reddy, in Prince, ed., THERABBIT AND EYE RESEARCH, C. C. Thomas, Springfield, Ill., 1964, p. 218.The relationship between the concentration of another analyte in a bodytissue or fluid and the concentration of the analyte in an ocular fluidcan be determined by methods well known in the art. See, for example,March et al, Diabetes Care 5, 259-65, 1982. The detector can beconfigured to convert the measurement of the analyte concentration intoa value which reflects the concentration of the analyte in the relevantbody tissue or fluid, e.g., blood.

[0033] If desired, the analyte sensor system also can comprise atransmitter configured to transmit a signal representing whether thedetectable label is detected and/or an amount of the detectable labelthat is detected. A device configured to vary the concentration of theanalyte in a body fluid or tissue, such as an infusion pump or otherpump, may receive the signal and may vary the concentration response tothe signal. The signal from the analyte sensor system may comprise acontinuous or discontinuous telemetry signal generated by the detector.The pump may, in response to the signal, adjust the levels of theanalyte in the body by providing the user with the appropriate amount ofa regulator moiety, such as insulin. Infusion pumps are well known inthe art for delivering a selected medication to a patient includinghumans and other animals in accordance with an administration schedulewhich can be preselected or, in some instances, preprogrammed. Pumps foruse in this invention can be worn externally or can be directlyimplanted into the body of a mammal, including a human, to deliver aspecific medication such as insulin to the mammal in controlled dosesover an extended period of time. Such pumps are well known and aredescribed, for example, in U.S. Pat. Nos. 5,957,890, 4,923,375,4,573,994, and 3,731,681. Medications which should optimally bemaintained at a constant level, such as phenobarbital, baclofen,theophylline, and cardiac and blood pressure medications, also can beprovided by means of an infusion pump.

[0034] Illustrative Embodiments

[0035] Illustrative embodiments of the analyte sensor system accordingto embodiments of the invention are shown in FIGS. 1 and 2. FIG. 1 is aschematic view of an analyte sensor system employing a contact lens 1, aradiation detector 5, such as a fluorophotometer, and a radiation source2, such as a laser (which preferably is of low power) or light emittingdiode, which emits light 3 with a first wavelength which will excite thefluorescent label in competitor moieties contained within the contactlens 1. In response to the light 3, competitor moieties which are notbound to receptor moieties will thereby emit light 4 of a seconddifferent wavelength (e.g., by fluorescence), which can be detected andmeasured by a radiation detector 5. The radiation detector 5 and theradiation source 2 may be embodied together as a hand-held unit, asshown in FIG. 1.

[0036] Conveniently, a miniaturized version of the radiation source 2and the radiation detector 5 can be configured to be built into a pairof eyeglasses. An exemplary embodiment of this is shown in FIGS. 2A and2B. The analyte sensor system shown in FIGS. 2A and 2B employs anintraocular lens 8, which comprises a polymer 9 containing receptormoieties and fluorescently labeled competitor moieties. A light-emittingdiode 6 is mounted in the frame of a pair of eyeglasses 7. Thelight-emitting diode 6 emits light 3 with a first wavelength which willexcite the fluorescent label in the competitor moieties. Competitormoieties which are not bound to receptor moieties will thereby emitlight 4 of a second different wavelength, which can be detected andmeasured by a fluorophotometer 5, which is mounted together with thelight-emitting diode 6 in the eyeglasses frame 7. A telemetry signal 10is transmitted to an infusion pump 11, which can provide a regulatormoiety, such as insulin, to maintain suitable levels of the analyte inthe body The telemetry signal 10 may be analog or digital and may betransmitted via wire or cable, such as wire 60, or wirelessly, such asvia radio frequency or infrared transmission. Where the telemetry signal10 is transmitted wirelessly, the analyte sensor system may includeantennas 50, 51, for such wireless transmission. Antenna 50 may, ifdesired, be embedded within eyeglass frame 7. As shown in FIG. 2C, theantennas 50, 51 may be coupled with a respective wireless transmitter 52and wireless receiver 53.

[0037] The telemetry signal 10 may include qualitative information as towhether or not the analyte is detected by the radiation detector 5. Forexample, where the detected light 4 is at or exceeds a predeterminedthreshold, the telemetry signal 10 may represent a “detected” state(such as the existence of telemetry signal 10). Where the detected light4 is below the threshold, the telemetry signal 10 may represent a “notdetected” state (such as the absence of telemetry signal 10).Alternatively, the telemetry signal 10 may indicate a change in analyteconcentration. Telemetry signal 10 also may provide a warning signal ifthe analyte concentration is above or below a preset range.

[0038] Optionally, the telemetry signal 10 may include quantitativeinformation as to how much light 4 is detected by the radiation detector5. For instance, the telemetry signal 10 may be varied in amplitudeand/or frequency responsive to the amount of light 4 detected, where theamplitude and/or frequency represents the amount of light 4. As anotherexample, the telemetry signal 10 may include digital data representingthe amount of detected light 4.

[0039] If the telemetry signal 10 is analog, the telemetry signal 10 maybe generated by the detector 5, which may include a modulator forgeneration of the telemetry signal 10. If the telemetry signal 10 isdigital, the telemetry signal 10 may be generated by ananalog-to-digital (“A/D”) converter 70. Also, the amount of the light 4detected by the radiation detector 5 may be shown on a display 71 (whichmay include a display driver), such as a CRT screen or liquid crystaldisplay (“LCD”).

[0040] All patents and patent applications cited in this disclosure areexpressly incorporated herein by reference. The above disclosuregenerally describes the present invention. A more complete understandingcan be obtained by reference to the following specific examples whichare provided for purposes of illustration only and are not intended tolimit the scope of the invention.

EXAMPLE 1

[0041] Construction of an Intraocular Glucose Sensor

[0042] A structurally stable polymer of polyethylene glycol hydrogel(PEGH, Shearwater Polymers, Inc.) is used to construct an intraocularglucose sensor. PEGH is immobilized in an intraocular lens (AlconLaboratories, 6 mm circumference, 1 mm thickness). Chemicallyimmobilized pendant tetramethylrhodamine isothiocyanate concanavalin A(TRITC-ConA, Sigma) is incorporated into the PEGH as the receptor moietyand fluorescein isothiocyanate dextran (FITC-dextran, Sigma) isincorporated as the competitor moiety by polymerization under UV light,as described by Ballerstadt & Schultz, Anal. Chim. Acta 345, 203-12,1997, and Russell & Pishko, Anal. Chem. 71, 3126-32, 1999. While theFITC-dextran is bound to the TRITC-ConA, the FITC fluorescence isquenched via a fluorescence resonance energy transfer. Increased glucoseconcentration frees the FITC-dextran and results in fluorescence whichis proportional to glucose concentration.

[0043]FIG. 4 shows the relationship between fluorescence intensity ofour fluorescent intraocular lens at three glucose concentrations invitro. A linearly proportional relationship occurs between 0 and 500 mg% at 518 nm, which is the peak of fluorescein fluorescence. The peak at575 nm is due to the rhodamine in the TRITC-ConA.

EXAMPLE 2

[0044] Implantation of an Intraocular Glucose Sensor In Vivo

[0045] The intraocular lens glucose sensor described in Example 1 isimplanted into the anterior chamber of the eye of a living New Zealandrabbit with a blood glucose concentration of 112 mg %. The implant isvisible as a bright spot of green fluorescence (518 nm) within the eye.

Careful examination with a biomicroscope slit lamp shows no sign oftoxicity, rejection, or any reaction 6 months after implantation:
 1. Anophthalmic lens for detecting an analyte in an ocular fluid, comprising:a receptor moiety which comprises an analyte/competitor moiety bindingsite.
 2. The ophthalmic lens of claim 1 which further comprises acompetitor moiety comprising a detectable label.
 3. The ophthalmic lensof claim 1 which is selected from the group consisting of a contactlens, an intraocular lens, a subconjunctival lens, and an intracorneallens.
 4. The ophthalmic lens of claim 1 , wherein the analyte isselected from the group consisting of an electrolyte, a metallicelement, a polypeptide hormone, a chronically administered medication,an acutely administered medication, a small molecule hormone, a markerof inflammation, a marker of allergy, a lipid, a protein, a marker ofinfection, and a metabolite.
 5. The ophthalmic lens of claim 1 , whereinthe ocular fluid is selected from the group consisting of tears, aqueoushumor, and interstitial fluid.
 6. The ophthalmic lens of claim 1 ,wherein the receptor moiety is covalently bound to the ophthalmic lens7. The ophthalmic lens of claim 2 which comprises a polymer meshwork,wherein pores of the polymer meshwork (a) permit the competitor moietyto bind reversibly to the analyte/-competitor moiety binding site and(b) prevent the receptor moiety and the competitor moiety from diffusingout of the ophthalmic lens.
 8. The ophthalmic lens of claim 2 whichcomprises: a receptor moiety layer; a polyelectrolyte layer; and acompetitor moiety layer
 9. The ophthalmic lens of claim 2 , wherein thedetectable label is a fluorescent label.
 10. An ophthalmic lens fordetecting glucose in an ocular fluid, comprising: a receptor moietylayer, wherein receptor moieties in the receptor moiety layer compriseglucose/competitor moiety binding sites; a first and a secondpolyelectrolyte layer; and a competitor moiety layer, wherein competitormoieties in the competitor moiety layer comprise detectable labels. 11.The ophthalmic lens of claim 10 , wherein the receptor moiety layercomprises concanavalin A molecules.
 12. The ophthalmic lens of claim 10, wherein the competitor moiety layer comprises fluorescein dextranmolecules.
 13. An analyte sensor system, comprising: (a) an ophthalmiclens for detecting an analyte in an ocular fluid, comprising: (i) areceptor moiety which comprises an analyte/competitor moiety bindingsite; and (ii) a competitor moiety comprising a detectable label; and(b) a detector configured to detect the detectable label.
 14. Theanalyte sensor system of claim 13 , wherein the detector includes afluorophotometer.
 15. The analyte sensor system of claim 13 , furthercomprising a transmitter coupled to the detector and configured totransmit to a pump a signal indicating whether the detectable label isdetected by the detector, wherein the pump is configured to vary aconcentration of the analyte in a body fluid or tissue.
 16. The analytesensor system of claim 15 , wherein the transmitter is contained in apersonal accessory.
 17. The analyte sensor system of claim 15 , furthercomprising the pump.
 18. The analyte sensor system of claim 15 , whereinthe transmitter is further configured to transmit the signal to the pumpwirelessly.
 19. The analyte sensor system of claim 15 , wherein theanalyte is glucose and the body fluid is blood.
 20. The analyte sensorsystem of claim 19 , wherein the receptor moiety is concanavalin A. 21.The analyte sensor system of claim 19 , wherein the competitor moiety isfluorescein dextran.
 22. The analyte sensor system of claim 19 , whereinthe pump is an insulin pump.
 23. The analyte sensor system of claim 13wherein the ophthalmic lens is selected from the group consisting of acontact lens, an intraocular lens, a subconjunctival lens, and anintracorneal lens.
 24. The analyte sensor system of claim 13 , whereinthe ophthalmic lens comprises a polymer meshwork, wherein pores of thepolymer meshwork (a) permit a competitor moiety to bind reversibly tothe analyte/competitor moiety binding site and (b) prevent the receptormoiety and the competitor moiety from diffusing out of the ophthalmiclens.
 25. The analyte sensor system of claim 13 , wherein the ophthalmiclens comprises: a receptor moiety layer; a polyelectrolyte layer; and acompetitor moiety layer.
 26. The ophthalmic lens of claim 13 , whereinthe ocular fluid is selected from the group consisting of tears, aqueoushumor, and interstitial fluid.
 27. A method for measuring theconcentration of an analyte in an ocular fluid, comprising the steps of:(a) contacting the ocular fluid with an ophthalmic lens, wherein theophthalmic lens comprises: (i) a receptor moiety which comprises ananalyte/competitor moiety binding site; and (ii) a competitor moietywhich comprises a detectable label; and (b) detecting the detectablelabel, wherein the amount of detectable label detected indicates theconcentration of the analyte in the ocular fluid.
 28. The method ofclaim 27 , wherein the ophthalmic lens is selected from the groupconsisting of a contact lens, an intraocular lens, a subconjunctivallens, and an intracorneal lens.
 29. The method of claim 27 , wherein theanalyte is selected from the group consisting of electrolytes and smallmolecules, metallic elements, polypeptide hormones, chronicallyadministered medications, acutely administered medications, smallmolecule hormones, markers of inflammation, markers of allergy, lipids,proteins, markers of infection, and metabolites.
 30. The method of claim27 , wherein the ocular fluid is selected from the group consisting oftears, aqueous humor, and interstitial fluid.
 31. The method of claim 27, wherein the receptor moiety is covalently bound to the ophthalmiclens.
 32. The method of claim 27 , wherein the ophthalmic lens comprisesa polymer meshwork, wherein pores in the polymer meshwork (a) permit acompetitor moiety to bind reversibly to the analyte/competitor moietybinding site and (b) prevent the receptor moiety and the competitormoiety from diffusing out of the ophthalmic lens.
 33. The method ofclaim 27 , wherein the ophthalmic lens comprises: a receptor moietylayer; a polyelectrolyte layer; and a competitor moiety layer.
 34. Themethod of claim 27 , wherein the detectable label is a fluorescentlabel.
 35. The method of claim 27 , wherein the ocular fluid is selectedfrom the group consisting of tears, aqueous humor, and interstitialfluid.
 36. A method for varying the concentration of an analyte in anocular fluid, comprising the steps of: (a) contacting the ocular fluidwith an ophthalmic lens, wherein the ophthalmic lens comprises: (i) acompetitor moiety which comprises a detectable label; and (ii) areceptor moiety which comprises an analytelcompetitor moiety bindingsite; (b) detecting the detectable label, wherein the amount ofdetectable label detected indicates the concentration of the analyte ina body tissue or fluid; (c) transmitting a signal indicating theconcentration of the analyte in the ocular fluid to a pump configured tovary the concentration of the analyte in the body tissue or fluid; and(d) providing a regulator moiety via the pump to the body tissue orfluid, whereby the concentration of the analyte in the body tissue orfluid is varied.
 37. The method of claim 36 wherein the detectable labelis a fluorescent label.
 38. The method of claim 37 wherein thedetectable label is detected by a fluorophotometer.
 39. The method ofclaim 38 wherein the fluorophotometer is contained in a personalaccessory.
 40. The method of claim 36 wherein the ocular fluid isselected from the group consisting of tears, aqueous humor, andinterstitial fluid.
 41. The method of claim 36 wherein the analyte isglucose.
 42. The method of claim 41 wherein the receptor moiety isconcanavalin A.
 43. The method of claim 41 wherein the competitor moietyis fluorescein dextran.
 44. The method of claim 41 wherein the regulatormoiety is insulin.
 45. The method of claim 36 wherein the ophthalmiclens is selected from the group consisting of a contact lens, anintraocular lens, a subconjunctival lens, and an intracorneal lens. 46.The method of claim 36 , wherein the receptor moiety is covalently boundto the ophthalmic lens.
 47. The method of claim 36 , wherein theophthalmic lens comprises a polymer meshwork, wherein pores of thepolymer meshwork (a) permit a competitor moiety to bind reversibly tothe analyte/competitor moiety binding site and (b) prevent the receptormoiety and the competitor moiety from diffusing out of the ophthalmiclens.
 48. The method of claim 36 , wherein the ophthalmic lenscomprises: a receptor moiety layer; a polyelectrolyte layer; and acompetitor moiety layer.
 49. A kit for detecting an analyte in an ocularfluid, comprising: an ophthalmic lens comprising a receptor moiety whichcomprises an analyte/competitor moiety binding site; and instructionsfor using the ophthalmic lens to detect the analyte.
 50. The kit ofclaim 49 , further comprising a competitor moiety comprising adetectable label.
 51. The kit of claim 49 , further comprising adetector configured to detect the detectable label.
 52. A kit fordetecting glucose in an ocular fluid, comprising: a contact lenscomprising concanavalin A and fluorescein dextran; and instructions forusing the contact lens to detect glucose in the ocular fluid.
 53. Thekit of claim 52 , further comprising a detector for detectingfluorescence of fluorescein dextran which is not bound to theconcanavalin A.